ORGANIC LETTERS
Total Synthesis of (−)-Callystatin A Neil F. Langille and James S. Panek*
2004 Vol. 6, No. 18 3203-3206
Department of Chemistry and Center for Chemical Methodology and Library DeVelopment, Metcalf Center for Science and Engineering, Boston UniVersity, 590 Commonwealth AVenue, Boston, Massachusetts 02215
[email protected] Received July 12, 2004
ABSTRACT
A convergent enantioselective synthesis of the natural product (−)-callystatin A (1) is described. Key features of the synthesis include a lipase-mediated kinetic resolution to install the C5 lactone stereochemistry, a hydrozirconation-based approach to the C8−C9 trisubstituted (Z)-olefin, and a stereoselective cross-coupling of a vinyl dibromide to install the C14−C15 trisubstituted (E)-olefin.
(-)-Callystatin A (1) is a polyketide-based natural product isolated in 1997 by Kobayashi and co-workers from the marine sponge Callyspongia truncata.1 Initial biological testing1,2 revealed remarkable antiproliferative properties (IC50 values 10 and 20 pg/mL vs KB and L1210 cell lines, respectively), derived from (-)-callystatin A’s ability to interfere with nuclear export signal (NES) dependent protein transport. Structure-activity relationship analysis indicates that the δ-lactone is the principle pharmacophore, although no enhancement of biological activity through analogue synthesis has been reported.3 (-)-Callystatin A’s potent cytotoxicity, along with its challenging structure, has stimulated much attention, culminating in seven total syntheses to date.4,5 Our retrosynthetic analysis of (-)-callystatin A (1) relies on bond disconnections at the two conjugated dienes, where (1) Kobayashi, M.; Higuchi, K.; Murakami, N.; Tajima, H.; Aoki, S. Tetrahedron Lett. 1997, 38, 2859-2862. (2) (a) Murakami, N.; Sugimoto, N.; Tsutsui, Y.; Nakajima, T.; Higuchi, K.; Aoki, S.; Yoshida, M.; Kudo, N.; Kobayashi, M. Abstracts of Papers, 41st Symposium on the Chemistry of Natural Products, Nagoya, October 1999, pp 229-234. (b) For a discussion of the biological activity of (-)-callystatin A, leptomycin, and related compounds, see: Kalesse, M.; Christmann, M. Synthesis 2002, 981-1003. (3) (a) Murakami, N.; Sugimoto, M.; Nakajima, T.; Kawanishi, M.; Tsutsui, Y.; Kobayashi, M. Bioorg. Med. Chem. 2000, 8, 2651-2661. (b) Murakami, N.; Sugimoto, M.; Kobayashi, M. Bioorg. Med. Chem. 2001, 9, 57-67. 10.1021/ol048664r CCC: $27.50 Published on Web 08/11/2004
© 2004 American Chemical Society
transition-metal-mediated cross-coupling reactions would enable assembly from three advanced intermediates at a late stage in the synthesis (Scheme 1). Fragment 3 possesses both a vinyl iodide equivalent (vinyl TMS) and a vinylstannane, thereby allowing carbon-carbon bond formation at C13C14 and C7-C8 in a predetermined sequence. A hydrozirconation-iodination protocol developed in our laboratory facilitates stereoselective installation of the C8-ethyl substituent in 3, where alkyne 6 serves as the appropriate starting material.6 Diene RCM provides access to lactol 2, with C7C8 bond formation planned through a tandem hydrozirconation-Negishi coupling protocol.7 Chiral organosilanemediated bond construction8 enables stereoselective synthesis (4) (a) Murakami, N.; Wang, W.; Aoki, M.; Tsutsui, Y.; Sugimoto, M.; Kobayashi, M. Tetrahedron Lett. 1998, 39, 2349-2352. (b) Crimmins, M. T.; King, B. W. J. Am. Chem. Soc. 1998, 120, 9084-9085. (c) Smith, A. B., III; Brandt, B. M. Org. Lett. 2001, 3, 1685-1688. (d) Kalesse, M.; Quitschalle, M.; Khandavalli, C. P.; Saeed, A. Org. Lett. 2001, 3, 31073109. (e) Marshall, J. A.; Bourbeau, M. P. J. Org. Chem. 2002, 67, 27512754. (f) Marshall, J. A.; Bourbeau, M. P. Org. Lett. 2002, 4, 3931-3934. (g) Vicario, J. L.; Job, A.; Wolberg, M.; Mu¨ller, M.; Enders, D. Org. Lett. 2002, 4, 1023-1026. (h) Lautens, M.; Stammers, T. A. Synthesis 2002, 1993-2012. (5) For additional studies toward fragment synthesis, see: (a) Dias, L. C.; Meira, P. R. R. Tetrahedron Lett. 2002, 43, 185-187. (b) Dias, L. C.; Meira, P. R. R. Tetrahedron Lett. 2002, 43, 1593. (c) Dias, L. C.; Meira, P. R. R. Tetrahedron Lett. 2002, 43, 8883-8885. (6) Arefolov, A.; Langille, N. F.; Panek, J. S. Org. Lett. 2001, 3, 32813284.
Scheme 1.
Retrosynthetic Analysis of (-)-Callystatin A (1)
of 4, with a Stille reaction proposed to form the C13-C14 bond.9 It is worthy to note that unlike other completed syntheses of (-)-callystatin A, our approach does not include a Still-Gennari reaction for the formation of the trisubstituted C8-C9 (Z)-alkene4a-h or a phosphorus-based olefination for the trisubstituted C14-C15 (E)-alkene.4a-c,g-h Grignard reaction between allylmagnesiumbromide and 910 initiated the synthesis of fragment 2 (Scheme 2), providing racemic propargyl alcohol 10 in excellent yield. Structural similarities between 10 and the known allylic alcohol 1311 suggested that this substrate might participate in an enantioselective kinetic resolution with lipase Pseudomonas AK,12
Scheme 2.
a
Synthesis of Lactol 2a
Reagents, conditions, and yields: (a) allylmagnesium bromide, THF, -20 °C, >99%; (b) vinyl acrylate, lipase AK, hexanes, 7 days, rt, 44% (-)-10, 46% 5; (c) DIAD, acrylic acid, PPh3, THF, 0 °C to rt, 86%; (d) Grubbs I, CH2Cl2, 40 °C, 83%; (e) DIBAL-H, -78 °C, CH2Cl2; (f) i-PrOH, PPTS, PhH, 80 °C, 82% (two steps); (g) 1.3:1 AcOH/TBAF, THF, rt, 91%. 3204
in the presence of the transesterifying agent vinyl acetate (Figure 1). As anticipated, 10 reacted under these conditions
Figure 1. Lipase Pseudomonas AK mediated kinetic resolution of 13 (eq 1, ref 11) and 10 in the presence of vinyl acetate (eq 2) and vinyl acrylate (eq 3).
to produce (R)-acetate 15 in 48% yield and >95% ee.13 With this result in hand, we hypothesized that a similar reaction in the presence of vinyl acrylate might resolve 10 with concomitant installation of the requisite acrylate ester on the desired (R)-enantiomer. Gratifyingly, this biocatalytic resolution proceeded with excellent stereoselectivity, providing (R)-5 directly in a one-pot process in 46% yield and >95% ee.13,14 Following chromatographic separation of 5 and (-)10, a Mitsunobu reaction transformed unreacted (-)-10 to 5 with complete stereochemical inversion. Rutheniumcatalyzed RCM,15 lactone protection as the isopropoxy acetal, and removal of the silicon protecting group completed the synthesis of 2 in a six-step sequence in 51% overall yield. The synthesis of fragment 3 from aldehyde 1616 commenced with a four-step sequence featuring a hydrozircona(7) (a) Negishi, E. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New York, 1998; Chapter 1. (b) For a related transformation, see: Jacobsen, E. N.; Chavez, D. E. Angew. Chem., Int. Ed. 2001, 40, 3667-3670. (8) For a review, see: Masse, C. E.; Panek, J. S. Chem. ReV. 1995, 95, 1293-1316. (9) Shen, W.; Wang, L. J. Org. Chem. 1999, 64, 8873-8879. (10) Journet, M.; Cai, D.; DiMichele, L. M.; Larsen, R. D. Tetrahedron Lett. 1998, 39, 6427-6428. (11) Sparks, M. A.; Panek, J. S. Tetrahedron Lett. 1991, 32, 40854088. (12) Pseudomonas AK lipase was purchased from Amano International Enzyme Co. (13) The ee of recovered (S)-10 was >95%. See the Supporting Information for full characterization and the stereochemical assignments of 5 and 15. (14) For an example of lipase-mediated acryloyl transfer, see: Bisht, K. S.; Gross, R. A.; Kaplan, D. L. J. Org. Chem. 1999, 64, 780-789. (15) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446-452. (16) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496-6511. Org. Lett., Vol. 6, No. 18, 2004
tion-iodination method6 for the installation of the requisite C8-ethyl substituent in the trans configuration (Scheme 3).
Scheme 3.
Scheme 4.
Synthesis of Vinyl Dibromide 4a
Synthesis of Vinyl Stannane 3a
a Reagents, conditions, and yields: (a) CBr , PPh , 2,6-lutidine, 4 3 CH2Cl2, 0 °C to rt, 96%; (b) n-BuLi, THF, -78 °C, then TMSCl, -78 °C to rt, 98%; (c) Cp2ZrHCl, THF, 50 °C, 1 h, then I2, THF, rt, 89%, >20:1 crude dr; (d) EtZnX, Pd(PPh3)4, THF, rt, 96%; (e) DDQ, CH2Cl2/H2O, rt, 83%; (f) (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C; 92%; (g) CrCl2, Bu3SnCHI2, DMF, 0 °C to rt, 68%, E/Z >20:1.
We have shown that upon exposure to an electrophilic iodine source (I2, NIS), iododesilylation of 18 occurred with retention of alkene configuration. However, we felt that elaboration of the benzyl ether moiety into the corresponding vinylstannane, prior to iodide formation and cross-coupling, would represent a more convergent approach. Accordingly, treatment of 18 with DDQ followed by Swern oxidation17 yielded aldehyde 19, which participated in a chromium(II)mediated vinylstannation18 with freshly prepared Bu3SnCHI2 to complete the preparation of 3 in seven steps from aldehyde 16. Organosilane reagents such as 7 provide rapid access to polypropionate fragments with high levels of selectivity. At first glance, the all-syn C16-C20 stereochemistry in (-)callystatin A is a readily accessible target, with the (R)configuration of 7 directing the C16 and C18 methyl stereocenters. Accordingly, our synthesis began with treatment of aldehyde 819 with (R)-7 in the presence of TiCl4 to yield homoallylic alcohol 20 as the syn-syn product in 84% yield (Scheme 4). Protection of 20 as a silyl ether and oxidative cleavage afforded aldehyde 21a, setting the stage for a second crotylation reaction. However, exposure of 21a to (R)-7 in the presence of TiCl4 produced homoallylic alcohol 20 in >80% yield, with no trace of desired alcohol 22a. We rationalize that a Lewis acid promoted deprotection-retroaldol-crotylation sequence led to exclusive formation of undesired 20. Indeed, the analogous reactions with other acid-sensitive ether protecting groups at C19 (OBn, OTES) yielded similar results.20 To alleviate this difficulty, (17) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651-1660. (18) (a) Hodgson, D. M.; Boulton, L. T.; Maw, G. N. Tetrahedron 1995, 51, 3713-3724. (b) Hodgson, D. M.; Foley, A. M.; Boulton, L. T.; Lovell, P. J.; Maw, G. N. J. Chem. Soc., Perkin Trans. 1 1999, 2911-2922. (19) White, J. D.; Bolton, D. L.; Dantanarayana, A. P.; Fox, C. M. J.; Hiner, R. N.; Jackson, R. W.; Sakuma, K.; Warrier, U. S. J. Am. Chem. Soc. 1995, 117, 1908-1939. (20) Hydroxy aldehyde (21, R ) H) displayed similar reactivity. Org. Lett., Vol. 6, No. 18, 2004
a Reagents, conditions, and yields: (a) (R)-7, TiCl , CH Cl , -30 4 2 2 °C, 84%, 10:1 crude dr; (b) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C to rt, 92%; (c) Ac2O, pyr, DMAP, CH2Cl2, rt, 99%; (d) O3, pyr, MeOH/CH2Cl2, -78 °C, then Me2S; (e) (R)-7, TiCl4, CH2Cl2, -30 °C, 21a to 22a: 0%; 21b to 22b: 68% (two steps), >20:1 crude dr; (f) CBr4, PPh3, 2,6-lutidine, CH2Cl2, 0 °C to rt, 82% (two steps); (g) K2CO3, MeOH, rt, 99%; (h) TIPSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 90%; (i) PCC, CH2Cl2, rt, 85%.
the acetate analogue 21b was synthesized and subjected to crotylation conditions. Although 21b proved remarkably unreactive, prolonged reaction time (-30 °C, 2 d) resulted in formation of the desired homologated alcohol 22b in good yield. Ozonolytic cleavage and dibromoolefination21 of the free alcohol22 directly provided 23, possessing the fragment’s full C14-C22 carbon skeleton. Concerned with removal of the C19 acetate at a late stage, we carried out a two-step protecting group exchange sequence to generate 25. Interestingly, TIPS protection of diol 24 proceeded with complete regioselectivity at C19, suggesting the different steric environments of the two alcohol functionalities. Oxidation of 25 using PCC completed the advanced fragment 4 in nine steps and 32% overall yield from 8. With access to the three advanced fragments, we envisioned the rapid assembly of (-)-callystatin A beginning with C13-C14 carbon-carbon bond formation (Scheme 5). A Pd2dba3-mediated cross-coupling9 between stannane 3 and dibromide 4 yielded vinyl bromide 26, with the desired (E,Z)diene as the only observed product isomer. Installation of the C14-methyl group by the Negishi protocol23 proceeded smoothly without epimerization or nucleophilic addition to the ketone. Treatment of 27 with the electrophilic iodine source NIS,24 however, resulted in undesired regioselective iodination of the C14-C15 olefin. Close inspection of the (21) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769-3772. (22) Unusual reactivity of similar intermediates has been reported. See refs 4a,e,f and 5b for details. (23) For application in related ene-yne systems, see: Shi, J.; Zeng, X.; Negishi, E. Org. Lett. 2003, 5, 1825-1828. (24) Stamos, D. P.; Taylor, A. G.; Kishi, Y. Tetrahedron Lett. 1996, 37, 8647-8650. 3205
Scheme 5.
Assembly and Completion of (-)-Callystatin Aa
Figure 2. 1H NMR chemical shifts (in ppm) as a measure of relative alkene electronegativity in 27 and 26. Upon exposure to NIS, highlighted alkenes undergo regioselective electrophilic iodination.
a
Reagents, conditions, and yields: (a) Pd2dba3, P(2-fur)3, PhMe, 100 °C, 92%; (b) Me2Zn, Pd(t-Bu3P)2, THF, 0 °C, 26 to 27: 96%; 28 to 29: 93%; (c) NIS, EtCN, 26 to 28: 84%; (d) (i) Cp2ZrHCl, THF, rt, (ii) ZnCl2, THF, (iii) 29, Pd(PPh3)4, rt, 51%; (e) AcOH, wet THF, rt; (f) PDC, CH2Cl2, rt, 74% (two steps); (g) HF/pyr, THF, rt, 88%.
1
H NMR spectrum of 27 (Figure 2) shows the electron-rich nature of the C14-C15 alkene relative to the C8-C9 olefin, explained by the strong donor capability of the C14-methyl substituent. Comparison to the 1H NMR spectrum of bromide 26, however, revealed the possibility of successful iododesilylation on this alternate substrate. Indeed, exposure of 26 to NIS resulted in regioselective addition of I+ to the C8 carbon, with retention of alkene stereochemistry. Iodo bromide 28 underwent regioselective bromide cross-coupling upon treatment with Me2Zn in the presence of Pd catalyst to form 29. We postulate that the electron-donating effect of the C8-ethyl group may deactivate the vinyl iodide, providing entry into oxidative addition of the relatively electron-deficient C14-bromide.25 In summary, this sequence provided fully functionalized iodide 29 in three steps from stannane 3 and vinyl dibromide 4. Subjection of 2 to Schwartz’s reagent followed by in situ treatment with ZnCl2 (25) For a discussion of electronic effects in Pd-mediated cross-couplings, see: Grushin, V. V.; Alper, H. Chem. ReV. 1994, 94, 1047-1062.
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produced a vinylzinc species that participated in a Pdcatalyzed Negishi coupling with 29 to afford the protected natural product 30 in 51% yield.26 Completion of the synthesis proceeded through AcOH-promoted lactol deprotection, oxidation, and fluoride-mediated removal of the silyl ether (65% over three steps). Synthetic (-)-callystatin A possesses spectroscopic properties identical to those reported for the natural product.1,4 In summary, we have developed an effective synthetic strategy for the total synthesis of (-)-callystatin A, utilizing cross-coupling reactions for the union of three highly functionalized fragments. The approach demonstrates the effectiveness of selective dibromide cross-coupling reactions and features a complimentary hydrozirconation-iodination approach for the stereoselective synthesis of trisubstituted alkenes. These methods should find utility in the synthesis of other related natural and unnatural molecules of biological importance. Acknowledgment. This work has been financially supported by the NIH (GM55740). J.S.P. is grateful to Johnson & Johnson, Merck Co., Amgen, Inc., Novartis, Pfizer, and GlaxoSmithKline for financial support. Supporting Information Available: Spectroscopic data and experimental procedures for all new compounds; key spectra. This material is available free of charge via the Internet at http://pubs.acs.org. OL048664R (26) Reproducibly, iodide 29 was recovered in 20-30% yield from this reaction. Attempts to increase iodide conversion to desired coupling product were unsuccessful.
Org. Lett., Vol. 6, No. 18, 2004
